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=RNase Mechanism=

Introduction
Acid Base Catalysis is the acceleration of a chemical reaction by the addition of an acid or a base and is mainly used in organic chemical reactions. The acid or base is not consumed in the reaction itself. An acid transfers protons to a reactant and a base accepts protons from the reactant. An acid is often thought of as a proton and the base as a hydroxyl. When the acids or bases donate or accept protons, they stabilize the developing charges in the transition state. This usually creates a better leaving group, making the reaction more energetically favorable. Additionally, this has an effect on the activity of the nucleophile and electrophile groups. Histidine is a very common residue involved in acid-base catalysis due to the fact that is has a pKa close to neutral; therefore, it can both accept and donate protons. The acid base mechanism can extensively alter the pKa depending on the environment of the residue. PKa will increase for an acidic residue if the environment is hydrophobic or if the adjacent residues are of similar charges. In the same environmental conditions, a basic residue will decrease the pKa. PKa will decrease for an acidic residue and increase for a basic residue if there is a salt bridge.

Acid Base Catalysis by RNase A
In the acid base catalysis of RNA in mammalians, RNase A catalyzes the cleavage of the P-O 5’ bond, and is comprised of two separate processes, the formation of … and subsequent…  An important part of the reaction is Histidine’s ability to both accept and donate electrons. This acts as a proton source, allowing Histidine to be utilized as a base or acid, making the reaction pH dependent.



The catalysis of RNase A begins when His-12 undergoes basic catalysis. H-12 will act as a base and abstract a proton from the RNA’s 2’ OH group; thus, assisting the attack on the phosphorus atom. Both reactions occur via transition states having a pentavalent phosphorous atom. These transition states are both stabilized by the side chain of Lys41 and the main chain of Phe120. This leads to the formation a stabilized 2’3’-cyclic intermediate. His-119 will support this reaction by protonating the leaving group, the 6’ OH on the ribose of the 3’ RNA, thus acting as a general acid. These products are then released into the surrounding solvent.

Next, the 2’,3’- cyclic nucleotide is hydrolyzed in a separate process. His-12 will donate a proton to the leaving group, the 3’ oxygen of the cyclic intermediate. Simultaneously, His-119 draws the hydrogen off of a water molecule. His 119 is thus reprotonated during this process, making water a better nucleophile. The water molecule attacks the phosphate causing the cleavage of the 2-3’ cyclic intermediate. The truncated nucleotide is then released with a 3’ phosphate group.



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